Diabetes 1 Notes

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Diabetes course notes (part 1)

1. Diabetes mellitus

Whats in a name?

1. Diabetes: Marching through urine is produced incessantly2. mellitus: honey-sweet as opposed to diabetes insipidus(insipid without flavour)

What does the adjective tell us about a traditional method of diagnosis?

Notes: The traditional method of diagnosis was exactly as suggested by the nomencla-

ture. It was effective, even if not entirely quantitative. For those of you who aspire to

medical school, it may be comforting to know that it is no longer in use.

2. Forms of diabetes mellitus

Type I, II, and secondary/symptomatic diabetes

Type I and II are somewhat similar: Lack of insulin effect lack of the hormone

(type I), or lack of functional response to the hormone (type II)

Symptomatic diabetes different; insulin still present, but antagonistic hormones

drive up glucose production. Typically acute clinical symptoms

Notes: Type I diabetes is the form typically observed in the young, whereas the type II

is more frequent overall and is typically observed in the elderly. MODY maturity type

onset diabetes of the young is type II diabetes in young people.

While the causation of diabetes type I is well understood and straightforward

destruction of the insulin-producing-cells of the pancreatic isletsour understanding

of type II diabetes is lagging behind. We will look at some recent science addressingthis question.

Symptomatic diabetes is diverse. A straightforward example is the excessive se-

cretion of glucagon by a glucagonoma, that is a benign tumor derived from glucagon-

secreting -cells in pancreatic islets. More commonly though it is caused by treatment

with high dosages of glucocorticoid hormones in the treatment of auto-immune dis-

eases.

3. Why is glucose lost through the kidneys?

Stages of urine production in the kidneys:

Filtration small molecules and ions are filtrated from the blood plasma at

150 liters/day

Salts and major metabolites reabsorbed by specific transporters

Capacity for glucose reuptake only slightly above the range of physiological blood

glucose values elevated levels of blood glucose will result in overflow

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4. Kidney tissue structure and function: Glomerulus and tubuli

Notes: The tissue slice shows a single glomerulus, and various tubular segments incross- or longitudinal sections.

5. Primary filtration occurs in the glomerulus

afferent arteriole

efferent arteriole

proximal tubule

Bowmans capsule

Notes: The blood pressure remains high throughout the glomerulus, meaning that

there is a driving force for filtration across the blood vessel walls. This explains the

extraordinarily large flow rate of filtration.

The filtration has a molecular weight cutoff of about 10 kDa. Therefore, all small

molecules and ions are filtrated, whereas large proteins such as proteins are retained

in the blood plasma. The appearance in the urine of proteins in significant amounts

indicates that the filtration apparatus is damaged, as is the case in an autoimmune

disease called glomerulonephritis.

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6. Reuptake and secretion occur in the tubular segments

Reuptake of

glucose, amino

acids,

bicarbonate,

Active secretion of uric acid,

organic acids, organic bases

Reuptake /

exchange of

ions; reuptake of

water

Filtration

Reuptake of weak organic

acids and bases

Notes: The bulk of the metabolites, including glucose, and most of the water are taken

up again in the proximal tubule of the nephron. The distal segments are concerned

with fine-tuning the concentration of the urine and the secretion or retention of salt

ions and protons according to the metabolic situation.

7. The capacity for glucose reuptake is saturated slightly above the physiological

plasma concentration range

Amount

filtrated

Plasma glucose concentration

Normal

range

Pathological

rangeAmount

excreted

Reabsorption maximum

Notes: The normal range of glucose in the blood is approximately 48 mM. Glucose

starts to appear in the urine when the plasma level exceeds 10 mM.

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8. Types of glucose transporters

Glc Glc

Glc Glc

Na+ Na+

SGLUT

GLUT

Notes: The sodium-coupled SGLT transporter is an example of secondary active trans-

port; it enables the uptake of glucose even against its concentration gradient. In the

intestinal, the sodium is secreted by the pancreas and the glands underneath the mu-

cosa of the small intestines.

The simpler GLUT transporter enables facilitated diffusion, which always occurs

downhill the concentration gradient. In most tissues, a low intracellular glucose con-

centration is maintained through the phosphorylation of glucose by hexokinase.

9. SGLT occurs at the luminal side of intestinal and kidney epithelia

GlucoseGlucose Glucose

2 Na+ 2 Na+

SGLT1 GLUT2

Notes: The occurence of SGLT at the intestinal and kidney epithelia ensures a virtually

complete uptake of glucose.

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10. The role of insulin in glucose transport

Active transport Facilitated transport

Intestine

Kidney tubules

Insulin-sensitive

Insulin-insensitive

Muscle

Fat

Most other tissues

Liver

Brain

Blood cells

Lens and cornea of eye

never

Notes: The brain must keep working and can take up glucose with or without insulin.

To preserve glucose when supply is low, its uptake into most other cell types occurs is

restricted by its dependence on insulin.

If blood glucose drops too low, a state called hypoglycemia, the brain will still

experience shortages, and unconsciousness will result.

11. Insulin promotes sugar uptake by increasing the number of surface-exposed

glucose transporters

Glucose

GlucoseHigh insulin Low insulin

cytoplasmic

membrane

Glucose transporter 4

stored intracellularly in vesicles

Glucose transporter 4

exposed on cell surface

Notes: This scheme only applies to those cell types in which glucose uptake is insulin-

dependent. As stated before, the brain and some other cell types are exempt.

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12. Where does glucose come from, and where does it go?

Sources:

1. Digested starch

2. Recovered from glycogen stores

3. Synthesized via gluconeogenesis

4. Converted from other carbohydrates: Fructose, galactose

Destinations:

1. ATP production

2. Biosynthesis (amino acids, nucleotides, . . . )

3. Glycogen synthesis

4. Triacylglycerol synthesis

13. Overview of glucose metabolism

H2

H2O

ADP + P

ATP

Acetyl-CoA

Pyruvate

glycolytic intermediates

Glucose Glycogen

Ribulose-5-P

Triacylglycerol

Starch, sugars

Amino acids

NH3

Urea

UC TCA

Notes: Looking at this slide is an opportunity for self-assessment. Do you understand

it? Can you identify the pathways responsible for these conversions? If not, it is advis-

able to repeat them. If you lack a textbook for doing so, you may want to look at my

Chem 333 metabolism course notes (available through the web).

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14. Structure of amylose/amylopectin

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2OH

OH

O

O

OH

OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2

OH

CH

OO

OH

OH

CH2OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2OH

OH

O

O

OH

OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2OH

O

O

OH

OH

CH2

OH

CH

Amylopectin is polyglucose, (14) glycosidic bonds; branches

formed by (14) glycosidic bonds. If no branches are present, the

molecule is called amylose.

Amylose and amylopectin are the two main components of starch,

which is the major storage carbohydrate of plants.

15. Digestion of amylose/amylopectin

Glucose Maltose

CH

O

CH

CH

CH

O

CH

OH

OH

OH

CH2OH

CH

O

CH

CH

CH

OH

CH

OH

OH

CH2OH

CH

O

CH

CH

CH

OH

CH

OH

OH

OH

CH2OH

Amylase cleaves amylose and amylopectin to the disaccharides maltose and iso-

maltose The brush border enzymes maltase and isomaltase produce monomeric glucose

Uptake occurs through the luminal SGLT transporter

Notes: In type II diabetics, one therapeutic strategy is to inhibit the maltase enzyme

with the drug acarbose, which results in a decreased rate of glucose uptake. Can you

imagine what kind of side effects this would have? Think of lactose tolerance.

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16. The brush border of the small intestine

Notes: The rate of substrate uptake from the intestine is proportional to its surface.

The surface is maximized at each level of organization: Length of the organ, folded

surface, decorated with macro- and microvilli.

17. The portal circulation

Liver

Liver vein

Systemic

circulation

Portal vein

Notes: The perfusion of the intestinal organs is organized differently from most other

organs, in that the blood drained from them is passed through the liver before being

fed back into the general circulation. The liver plays a key role in metabolic regulation;

it also protects the organism from ingested poisons.

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18. Metabolic fates of glucose

1. Immediate utilization: Glycolysis, pentose phosphate shunt

2. Conversion for storage: Glycogen synthesis, triacylglycerol synthesis

The distribution of glucose between these destinations depends on our metabolic state:

If free glucose is plentiful, both immediate utilization and conversion for storage

are enhanced. This is promoted by insulin

If free glucose is in high demand, utilization is restricted to preferred cus-

tomers, particularly the brain. This usage is promoted by glucagon and

epinephrin

19. Glycolysis and gluconeogenesis

Gluconeogenesis uses

the reversible reactions

from glycolysis andbypasses the

irreversible ones

Glycolysis only

Gluconeogenesis only

Shared

Glucose

Glucose-6-P

Fructose-6-P

Fructose-1,6-bis-P

Dihydroxyacetone-P +

Glyceraldehyde-P

1,3-Bis-P-glycerate

3-P-glycerate

P-enolpyruvate

Pyruvate

Oxaloacetate

2-P-glycerate

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20. Substrate sources for gluconeogenesis

es for

esisPyruvate

Acetyl-CoACO2

Citrate

Isocitrate

-Ketoglutarate

Succinyl-CoASuccinate

Fumarate

Malate

Oxaloacetate

CO2

CO2

Amino acids

P-enolpyruvate

Lactate, amino acids

Glucose

Notes: Amino acids that are converted to pyruvate or TCA intermediates and therefore

can serve as substrates for gluconeogenesis are called glucogenic. Leucine, lysine and

the aromatic amino acids are degraded to acetyl-CoA and/or acetoacetate. Since the

latter are, or can be converted to ketone bodies, these amino acids are called ketogenic.

21. Glycolysis and gluconeogenesis: Allosteric regulation of key enzymes

Fructose-6-P

Fructose-1,6-bis-P

ATP

ADPH2O

Pi

PFK 1Fructose-1,6

bisphosphatase

ATP

AMP

Fructose-2,6-bis-P

+

+

+

-

-

-

Glycolysis Gluconeogenesis

Notes: The regulatory molecule fructose-2,6-bisphosphate is controlled by hormones

(see below). Hormones communicate the metabolic demands of the entire organism (see

below). In contrast, ATP and AMP reflect the metabolic situation of the cell itself. Thus,

the allosteric regulation of PFP-1 and fructose-1,6-bisphosphatase strikes a compromise

between the needs of the individual cell and those of the organism as a whole.

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22. Fructose-bisphosphates compared

PO

O

OH

OO

OH

OH

CH2

OH

O

P OH

O

O

CH2

OHO

OH

OH

CH2

O

O

P OH

O

O

CH2

POH

O

O

Fructose-1,6-bisphosphate Fructose-2,6-bisphosphate

Notes: Fructose-2,6-bisphosphate is present at much lower levels than the 1,6-

bisphosphate and only exists for the purpose of regulation.

23. The level of Fructose-2,6-bisphosphate is under hormonal control

cAMP

+

Protein kinase A

PFK-2/bis-Pase PFK-2/bis-Pase

P

Fructose-6-P

Fructose-2,6-bis-P

+ -Epinephrin,

glucagonInsulin

Glycolysis

Gluconeogenesis

Notes: The phosphofructokinase 2 (PFK-2) and fructose-2,6-bisphosphatase enzyme

activities are located on the same bifunctional enzyme molecule. The phosphorylation

by protein kinase A activates the phosphatase activity and at the same time inhibits the

kinase activity.

Regulation by phosphorylation is best thought of as allosteric regulation, where the

allosteric effector happens to be covalently bound to the enzyme.

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24. Glycogen metabolism

Why store glucose in polymeric form?

In the liver, glycogen accounts for up to 10% of wet weight, which corresponds to 600

mM of glucose. According to

pV= nRT or p =n

VRT

this would roughly triple the osmotic activity of the liver cytosol cells would swell

and burst.

Linking 2 (3, ..) molecules of glucose divides the osmotic effect by 2 (3, ..) and makes

storage of large amounts of glucose compatible with physiological osmolarity.

Notes: The proportionality of concentration and osmotic activity does not strictly apply

at very large molecular weights.

25. Structure of glycogen

GlycogeninO-TyrO O O O O OO

O O O OO O

CH2

O O O O O

CH2

O O O O O

CH2

Linear polymers of(14)-linked

glucose residues, branched by

(16)-glycosidic bonds

6-8 glc residues total: > 105 glc residues

Notes: The structure of glycogen is essentially the same as that of amylopectin. How-

ever, the density of branches is greater, which means that a glycogen molecule has

a greater number of free ends than an amylopectin molecule of the same molecularweight. The number of free ends determine the possible rates of synthesis and break-

down, and the higher density in glycogen reflects the metabolic rate that is higher in

humans than in plants.

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26. The glycogen synthase reaction

O

OH

OH

OH

CH2OH

O GlycogeninTyr

GlycogeninO-TyrHO O O O O O

UDP-glc UDP-glc UDP-glc UDP-glc

UDP UDP UDP UDP UDP

UDP-glc

Notes: Glycogenin is a small protein that serves as the starter substrate for glycogen

synthesis.This is just to remind you what glycogen synthase does nothing new here, move

along.

27. The glycogen phosphorylase reaction

Pi

glc-1-P

glcglcglcglcglcglcglcglc

Pi

glcglcglcglcglcglcglcglcglcglcglcglcglcglc

glc-6-P glucose

glc-1-P

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28. Allosteric regulation of glycogen synthase and phosphorylase

Glycogen

Glucose-1-P

UDP-glucose

phosphorylaseglycogen

synthase ATP -

AMP +

Glc-6-P+ -

Glucose-6-P

Notes: Glucose-1-phosphate is reversibly converted to glucose-6-phosphate by phos-

phoglucomutase. The conversion of glucose-1-phosphate to UDP-glucose by glucose-1-phosphate uridyltransferase requires UTP and releases pyrophosphate.

29. Regulation of glycogen metabolism (2)

Epinephrine,

Glucagon

ATP

cAMP

Protein Kinase A

Glycogensynthase (active)

GlycogensynthaseP (inactive)

Phosphorylase

kinase (inactive)Phosphorylase

kinaseP (active)

Phosphorylase

(inactive)

Phosphorylase-P

(active)

Insulin

Notes: The upper part of this regulatory cascade is the same as in shown before for

gluconeogenesis. Glycogen metabolism and gluconeogenesis are therefore regulated in

parallel. In both cases, the effect of glucagon is to increase the rate of glucose synthesis

and to reduce the rate of consumption, whereas the effect of insulin in both cases is

the opposite.

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Diabetes 1 Notes

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